Project Summary Brain metastases, the most common malignant intracranial tumors, occur in up to 40% of patients with cancer. Left untreated, prognosis is abysmal, with a life expectancy of 1 month. Surgery and radiation are typically combined to treat brain metastases; however, with improved treatment of primary cancers, survival for some groups of patients with brain metastases has increased such that alternatives are being sought that minimize or avoid the risks of invasive surgery and the toxic effects of radiation to the brain. Although stereotactic radiation is increasingly used to limit the side effects of whole brain radiation, tumor control may not be as effective with stereotactic surgery alone. One possible alternative, magnetic resonance guided focused ultrasound, is being researched as a noninvasive means of ablating brain tumors and of increasing delivery of cancer therapeutics through the blood-brain barrier. Conventional techniques to transmit ultrasound into the brain have traditionally been implemented by means of a large-aperture spherical transducer consisting of a very large number of single element transducers transmitting ultrasound beams through the skull. The geometric focus of these transducers limits the treatment envelope to the center of the brain, whereas the majority of cancers, especially metastases, occur along the periphery of the brain. In addition, the skull significantly attenuates ultrasound. In order to compensate for the attenuated energy in the skull and achieve a sufficient deliverable power at the focus, the surface pressure of the transducer (i.e., input power) must be kept sufficiently high. High absorption at even moderate input powers leads to excess heating inside the skull, requiring active cooling to prevent burning of the bone or skin. To address the difficulties outlined above, we propose to develop a novel wedge transducer array technology for introducing focused ultrasound waves into the brain. The array couples ultrasound into the brain through double mode conversion: from longitudinal wave in the wedge to a high order Lamb wave in the skull, then from the high order Lamb wave in the skull to a longitudinal wave in the brain. The benefits of our approach are in improved efficiency, reduction in heating of the skull, the ability to address regions in the brain that are close to the skull, and freedom in operating at a wider range of frequencies. Therapy and neuro-modulation applications using this type of coupling technology will still rely on an imaging modality such as MR to ascertain the location and quality of the focus, and feedback control on the various wedges will be used to control the size and location of the focal spot in the brain, similar to what is done today with conventional approaches to trans- cranial ultrasound. The specific aims of the proposed work are as follows: (1) Develop three-dimensional in-silico models of transcranial ultrasound to be utilized in the design and optimization of wedge transducers. (2) Develop electronics feedback control system allowing control of transducer parameters to correct for beam aberration and defocusing. (3) Build, characterize, and benchmark MR-compatible wedge transducers on real human skull.